1-piperazinylpyrimidine derivatives and application thereof in therapeutics and cosmetics

ABSTRACT

New compounds derived from 1-piperazinylpyrimidine derivatives, and their application in therapeutics and cosmetics, corresponding to the general formula: ##STR1## in which R represents an alkoxycarbonyl group containing from 1 to 3 carbon atoms in the alkoxy chain or alternatively a furoyl group, n being 0 or 1, and their addition salts with cosmetically or pharmaceutically acceptable acids.

The invention relates to new compounds derived from1-piperazinylpyrimidine and to the application thereof in therapeuticsand cosmetics, especially in compositions for inducing and stimulatinghair growth and for decreasing hair loss.

Man has a basic number of 100,000 to 150,000 hairs and it is normal tolose 50 to 100 daily. The maintenance of this basic number resultsessentially from the fact that the life of a hair is subjected to acycle called pilar cycle during which the hair is formed, it grows andfalls before being replaced by a new part which appears in the samefollicle.

In the course of a pilar cycle, three successive phases are observed:viz. the anagen phase, the catagen phase and the telogen phase.

During the first phase, referred to as the anagen phase, the hair passesthrough an active growth period associated with an intense metabolicactivity in the bulb region.

The second phase, referred to as the catagen phase, is transitory and itis marked by a slowing down of mitotic activities. During this phase,the hair undergoes an involution, the follicle atrophies and itsimplantation in the skin appears increasingly shallow.

The final phase, referred to as the telogen phase, corresponds to a restperiod for the follicle and the hair finally falls out, pushed by anewly formed anagen hair.

This constant physical renewal process undergoes a natural change duringageing, the hair becomes finer and the cycles thereof become shorter.

Alopecia results when this physical renewal process is accelerated ordisturbed, i.e. the growth phases become shorter, the passage of hairinto the telogen phase is earlier and hairs fall in larger numbers; thesuccessive growth cycles result in increasingly fine and increasinglyshort hairs, which are slowly converted into an unpigmented fluff. Thisphenomenon may lead to baldness.

The pilar cycle depends on many factors capable of leading to a more orless pronounced alopecia. Among these factors, there may be mentionednutritional factors, endocrinal factors, and nervous factors. Thechanges in the different categories of hair may be determined with atrichogram, especially a phototrichogram.

Compositions which enable the effect of alopecia to be eliminated orreduced and especially hair growth to be induced or stimulated or hairloss to be reduced have been sought in the cosmetic or pharmaceuticalindustry for many years.

To this end, compounds such as6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine and thederivatives thereof have already been proposed. Such compounds aredescribed especially in the patent U.S. Pat. No. 4,139,619.

The combination of retinoids with the abovenamed compounds has also beenproposed in the patent WO-A-83/02,558.

The Applicant Company has discovered that some 1-piperazinylpyrimidinederivatives could, in a surprising way, induce and stimulate hair growthand decrease their loss.

1-Piperazinylpyrimidine derivatives are already known, especially fromthe U.S. Pat. No. 3,644,364 and 3,910,928 and from the article publishedin Chemical Abstracts 97 : 198 165b.

These compounds are known in particular for their therapeuticproperties, especially in the cardiovascular field as antihypertensives.

The Applicant Company has prepared new compounds derived from1-piperazinylpyrimidine and has discovered that when they were employedin local application, they had a surprising activity on hair regrowthand enabled the growth of the latter to be induced or stimulated andtheir loss to be decreased.

Therefore, a first subject of the invention consists of new1-piperazinylpyrimidine derivatives and the preparation thereof.

Another subject of the invention consists of a therapeutic or cosmeticcomposition which enables, in particular, hair growth to be induced andstimulated and their loss to be decreased.

Another subject of the invention consists of the use of these compoundsin the preparation of a composition having a therapeutic effect withregard to the induction and the stimulation of hair growth.

Other subjects of the invention will become apparent on reading thedescription and the examples which follow.

The new compounds of the invention correspond to the general formula I:##STR2## in which R represents an alkoxycarbonyl group containing from 1to 3 carbon atoms in the alkoxy chain, or alternatively a furoyl groupand n is 0 or 1. In the case where n=1, the compounds may optionally bein the tautomeric form, one of the hydrogen atoms of an amino group inposition 2 or 4 migrating towards the oxygen atom, according to thefollowing scheme: ##STR3##

The invention also includes the addition salts that these compounds mayform with pharmaceutically or cosmetically acceptable acids.

According to the invention, these compounds may be prepared according tothe reaction scheme below.

An optionally N-oxidized pyrimidine of formula II in which X representsa halogen atom, preferably chlorine, is reacted with a piperazine offormula III in which R has the meaning given above, in the heated stateand optionally in the presence of a solvent such as chlorobenzene. Theacid HX which is also formed during this condensation enables theaddition salt of a compound of formula I to be obtained directly.##STR4##

The composition according to the invention is essentially characterizedin that it contains, in a pharmaceutically or cosmetically acceptablemedium, at least one compound corresponding to formula I above, as wellas its addition salts with pharmaceutically or cosmetically acceptableacids.

The particularly preferred compounds which can be used according to theinvention are those corresponding to formula (I) in which n=O and Rrepresents an ethoxycarbonyl or 2-furoyl group or alternatively n=1 andR represents an ethoxycarbonyl group.

There may be mentioned, in particular, ethyl4-(2,4-diamino-3-oxy-6-pyrimidinyl)piperazinecarboxylate, ethyl4-(2,4-diamino-6-pyrimidinyl)piperazinecarboxylate,4-(2,4-diamino-6-pyrimidinyl)-1-(2-furoyl)piperazine and especiallytheir hydrochlorides.

The compositions for local application according to the inventioncontain the compound of formula (I) in proportions of between 0.01 and15 % by weight relative to the total weight of the composition andpreferably between 0.1 and 10 % by weight.

A particularly preferred composition is that containing themonohydrochloride of alkyl4-(2,4-diamino6-pyrimidinyl)piperazinecarboxylate in proportions ofbetween 0.1 and 5 %.

According to an advantageous embodiment of the invention, the compoundof formula (I) may be combined with a pyrimidine derivative having aneffect on hair regrowth and more particularly6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine which isalso known under the name "Minoxidil", or alternatively a retinoid suchas those described in the application No. WO-82/02,833 or a combinationof the two.

Among the particularly preferred retinoids, there may be mentioned,all-trans-retinoic acid and 13-cisretinoic acid and theirphysiologically (pharmaceutically or cosmetically) acceptable salts oresters.

These compounds, when they are present, are employed in proportionswhich may range between 0.01 and 10 % by weight for the pyrimidinederivatives and between 0.001 and 2 % by weight for the retinoids.

These compounds may be employed in the same composition as the compoundof formula (I), or applied separately, either simultaneously or with atime lapse, before or after the composition containing the compound offormula (I).

The compositions according to the invention may be in the form oflotions, emulsions, creams or gels and may optionally be pressurized inthe form of an aerosol. They may be applied especially in treatmentswhich employ a composition as defined below, the application of which isfollowed or not followed by a rinsing, or alternatively in the form of ashampoo.

The cosmetically or pharmaceutically acceptable medium may consist of athickened or unthickened aqueous, aqueous/alcoholic or alcoholic medium,which may contain one or more cosmetically or pharmaceuticallyacceptable solvents.

The solvents are preferably chosen from amongst C₁ -C₄ lower alcoholssuch as ethyl alcohol, isopropyl alcohol and tert-butyl alcohol;alkylene glycols such as propylene glycol and mono- and dialkyleneglycol alkyl ethers such as ethylene glycol monoethyl ether, propyleneglycol monomethyl ether and diethylene glycol monethyl ether.

These compositions may contain other adjuvants which are commonlyemployed in the cosmetic or pharmaceutical field in order to preparecompositions for local application, such as, more particularly,surfactants, thickeners, preservatives and alkalinizing or acidifyingagents. The pH of these compositions may vary between 3 and 9 andpreferably between 5 and 8.

The thickening or gelling agents, may more particularly be chosen fromamongst heterobiopolysaccharides such as, for example, those containingmannose, glucose, glucuronic acid or galacturonic acid units in theirchains and more particularly xanthan gums and scleroglucans.

Among these products, there may be mentioned, those marketed under thename KELTROL T or TF, KELZAN S, KELZAN K9C57, KELZAN K8B12 and KELZANK3B130, marketed by KELCO; the products sold under the name RHODOPOL 23and 23SC or alternatively RHODIGEL 23 by RHONE POULENC; the productmarketed under the name DEUTERON XG by SCHONER GmbH and the productsmarketed under the name ACTIGUM CX9, CS11 and C56 by CECA/SATIA; otherheterobiopolysaccharides which may be employed are described, by way ofillustration, in the patent applications EP-A No.23,397, UK-ANo.2,058,106, UK-A No.2,058,107, U.S. Pat. No. 4,454,316, EP No.A-64,354 and DE-A No. 3,224,547.

Other gelling agents may be chosen from amongst cellulose derivativessuch as methylcellulose, hydroxymethylcellulose, carboxymethylcellulose,hydroxybutylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,methylhydroxyethylcellulose and methylhydroxypropylcellulose. Thesethickening or gelling agents are preferably employed in proportions from0.5 to 5 % and especially from 1 to 3 % by weight relative to the totalweight of the composition.

However, the thickening agents which may be employed may be chosen fromamongst polyacrylic acids crosslinked by a polyfunctional agent, such asthe products sold under the name CARBOPOL by GOODRICH or the thickenersresulting from the ionic interaction of a cationic polymer consisting ofa cellulose copolymer or of a cellulose derivative grafted with awater-soluble quaternary ammonium monomer salt and a carboxylic anionicpolymer. Among the latter substances, there may be mentioned, moreparticularly, the thickeners resulting from the interaction of acopolymer of hyroxyalkylcellulose grafted, by the radical method, with amethacryloylethyl trimethylammonium, methacrylamidopropyltrimethylammonium of dimethyl diallylammonium salt and a carboxylicanionic polymer chosen from amongst the homopolymers of methacrylicacid, the copolymers of methacrylic acid with a monomer chosen fromamongst C₁ -C₄ alkyl acrylates or methacrylates, acrylamide derivatives,maleic acid, C₁ -C₄ alkyl monomaleates, vinylpyrrolidone and thecopolymers of ethylene and maleic anhydride. The gravimetric ratiobetween the cationic polymer and the carboxylic anionic polymer isbetween 1:5 and 5:1.

The thickening agents are employed in proportions of between 0.5 and 2 %and preferably between 0.7 and 1.5 % by weight relative to the totalweight of the composition.

The treatment for the control of hair loss mainly consists in applyingto the alopecic regions of the scalp and the hair of an individual, acomposition as defined above, for example after washing the scalp andthe hair with a shampoo or shortly after shampooing. The preferredmethod of application consists in applying 1 to 2 g of the compositionaccording to the invention to the alopecic region having a surface areaof 200 to 300 cm² of scalp, at a frequency of 1 to 2 applications perday for 1 to 7 days per week.

The efficiency of the treatment is monitored once a month using aphototrichogram.

The use of the compounds of the formula (I) for the preparation of acomposition having an effect of inducing and stimulating hair growth andchecking their loss also forms the subject of the invention.

The treatment method has the features of a cosmetic method insofar as itenables the hair and the scalp to be cared for in the cosmetic sense ofthe term, i.e. to supply them with substances they lack and to beautifythem.

Moreover, the method has the features of a therapeutic treatment insofaras the active substance has a therapeutic activity with regard to thebiological mechanisms of the pilar cycle.

The following examples are intended to illustrate the invention without,however, being limiting in nature.

EXAMPLES OF PREPARATION 1

Ethyl 4-(2,4-diamino-6-pyrimidinyl)piperazinecarboxylatemonohydrochloride

10 g (0.069 mole) of 6-chloro-2,4-diaminopyrimidine and 21.8 g (0.138mole) of ethyl piperazine-1carboxylate are introduced into a conicalflask equipped with a magnetic stirrer and a reflux condenser and placedunder a nitrogen atmosphere. 75 ml of chlorobenzene are added and themixture is heated under reflux for 1 hour 30 minutes.

A precipitate is formed, which is filtered in the heated state, rinsedwith chlorobenzene and then with ether, and recrystallized in ethanol.

Melting point: 256° C. (ethanol)

    ______________________________________                                        Elemental analysis: C.sub.11 H.sub.19 ClN.sub.6 O.sub.2                                M = 302.76                                                                      C        H      N      O    Cl                                     ______________________________________                                        Calculated %                                                                             43.63    6.28   27.77  10.58                                                                              11.73                                  Found %    43.43    6.21   27.54  10.85                                                                              11.82                                  ______________________________________                                    

EXAMPLE OF PREPARATION 2

1-(2,4-diamino-6-pyrimidinyl)-4-(2-furoyl)piperazine monohydrochloride

A mixture of 4 g (0.0277 mole) of 6-chloro-2,4-diaminopyrimidine, 5 g(0.0277 mole) of 1-(2-furoyl)piperazine and 50 ml of chlorobenzene isheated under reflux for 5 hours.

A precipitate is formed, which is isolated in the heated state byfiltration. It is washed with chlorobenzene and then with ether and isrecrystallized in methanol.

Melting point: 295° C.(methanol).______________________________________Elemental analysis: C₁₃H₁₇ ClN₆ O₂ M = 324.5 C H N OCl______________________________________Calculated % 48.07 5.24 25.899.86 10.94Found % 48.13 5.26 25.80 10.0911.09______________________________________

EXAMPLE OF PREPARATION 3 Ethyl4-(2,4-diamino-3-oxy-6-pyrimidinyl)piperazinecarboxylatemonohydrochloride

10 g (0.063 mole) of 6-chloro-3-oxy-2,4-diaminopyrimidine and 30 g(0.190 mole) of ethyl piperazine-1-carboxylate are introduced into aconical flask equipped with a magnetic stirrer and a reflux condenserand placed under a nitrogen atmosphere. The mixture is heated to 100° C.in the course of 1 hour and maintained at this temperature for 1 hour 30minutes.

Approximately 30 ml of water are added to the hot mixture, the whiteprecipate formed is separated, it is washed with water and then withether and it is recrystallized in isopropyl alcohol.

The base thus obtained is dissolved in a minimum of ethanol and anexcess of ethereal hydrogen chloride is added to the solution. Thehydrochloride precipitate is separated and is crystallized in ethanol.

Melting point: 215° C.(ethanol)______________________________________elemental analysis: C₁₁H₁₉ ClN₆ O₃ M = 318.76 C H N OCl______________________________________Calculated % 41.48 5.96 26.3515.06 11.13Found % 41.48 5.95 26.28 14.8711.21______________________________________

The micro analysis and the IR and NMR spectrum confirm the structure ofthe compounds obtained in the preparation examples.

EXAMPLE OF FORMULATION 1

A lotion, active on the growth of hair and drecreasing hair loss isprepared:______________________________________Ethyl4-(2,4-diamino-6-pyrimidinyl) piperazine 4 gcarboxylatemonohydrochloridePreservative, perfume qsEthyl alcohol (70% solution) qs100 g______________________________________

The activity of the composition for stimulating hair growth is evaluatedover a placebo by applying 1 ml of this composition once a day on thealopecic area of the hair scalp of five persons having a mean age of 40years.

After a treatment of several months, the composition improvesefficiently the condition of the hair.

EXAMPLE OF FORMULATION2______________________________________4(2,4-diamino-6-pyrimidinyl)-1-(2-furoyl)2 gpiperazine monohydrochlorideDiethyleneglycol monoethyl ether 20gEthyl alcohol 40,5 gWater qs 100,00g______________________________________

This lotion is applied as indicated in example 1 and similar results arenoticed.______________________________________EXAMPLES OF FORMULATION 34______________________________________Ethyl 4-(2,4-diamino-3-oxy-6- 33pyrimidinyl) piperazinecarboxylatemonohydrochlorideHeteropolysaccharide 1in g AS KeltrolTHydroxypropylcellulose 3in g AS Klucel GIsopropyl alcohol 39.5ingTert-butyl alcohol 39.5in gWater 100 100qs ing______________________________________

When applied to the alopecic parts of the scalp, these compositionsenable an improvement to be observed in the condition of the hair.

EXAMPLE OF FORMULATION 5

A lotion having the following composition isprepared:______________________________________Ethyl4-(2,4-diamino-6-pyrimidinyl)- 3.00 gpiperazine carboxylatemonohydrochloridePropylene glycol 20.00 gEthyl alcohol 50.00 gWater qs100.00 g______________________________________

When applied to the alopecic parts of the scalp, this lotion enables thecondition of the scalp to be improved.

EXAMPLE OF FORMULATION 6

A lotion having the following composition isprepared:______________________________________Ethyl4-(2,4-diamino-6-pyrimidinyl)- 2.50 gpiperazine carboxylatemonohydrochlorideMinoxidil 1.00 gPropylene glycol 20.00 gEthyl alcohol50.00 gWater qs 100.00 g______________________________________

When applied as mentioned in Example 1, to the alopecic part of thescalp, a stimulation of hair regrowth is observed.

EXAMPLE OF FORMULATION 7

A lotion having the following composition isprepared:______________________________________13-cis-retinoic acid0.0125 gEthyl 4-(2,4-diamino-3-oxy-6-pyrimidinyl) 3.00 gpiperazinecarboxylate monohydrochlorideEthyl alcohol 95.00 gPropylene glycol qs100.00 g______________________________________

When applied as mentioned in Example 1, to the alopecic parts of thescalp, a stimulation of hair regrowth is observed.

EXAMPLE OF FORMULATION 8

A gel having the following composition isprepared:______________________________________Trans-retinoic acid 0.025gEthyl 4-(2,4-diamino-3-oxy-6-pyrimidinyl)- 3.00 gpiperazine carboxylatemonohydrochlorideEthyl alcohol 50.00 gWater 13.00 gAcrylic acidhomopolymer crosslinked by a 1.00 gpolyfunctional agent, sold under thenameCARBOPOL 940Triethanolamine qs pH = 5Preservative qsPropylene glycolqs 100.00 g______________________________________

EXAMPLE OF FORMULATION 9

A lotion having the following composition isprepared:______________________________________Ethyl4-(2,4-diamino-6-pyrimidinyl)- 3.00 gpiperazine carboxylatemonohydrochloride13-cis-retinoic acid 0.0125 gEthyl alcohol 95.00gPropylene glycol qs 100.00 g______________________________________

When applied as mentioned in Example 1 to the alopecic part of thescalp, a stimulation of hair regrowth is observed.

EXAMPLE OF FORMULATION 10

A gel having the following composition isprepared:______________________________________Ethyl4-(2,4-diamino-6-pyrimidinyl)- 3.00 gpiperazinecarboxylatemonohydrochlorideTrans-retinoic acid 0.025 gEthyl alcohol 50.00 gWater13.00 gAcrylic acid homopolymer crosslinked by 1.00 ga polyfunctionalagent, sold under thename CARBOPOL 940Triethanolamine qs pH =5Preservative qsPropylene glycol qs 100.00g______________________________________

When applied as mentioned in Example 1 to the alopecic part of thescalp, a stimulation of hair regrowth is observed.

We claim:
 1. Compounds corresponding to the formula (I): ##STR5## inwhich R represents an alkoxycarbonyl group having from 1 to 3 carbonatoms in the alkoxy chain or represents a furoyl group, n is 0 or 1, andtheir acid addition salts.
 2. Compounds according to claim 1, selectedfrom the group comprising of ethyl4-(2,4-diamino-6-pyrimidinyl)piperazinecarboxylate,4-(2,4-diamino-6-pyrimidinyl)-1-(2-furoyl)piperazine, ethyl4-(2,4-diamino-3-oxy-6-pyrimidinyl)piperazinecarboxylate and theirhydrochlorides.
 3. Composition to be used for the treatment of the scalpand hair for inducing and stimulating hair growth and for decreasinghair loss containing an excipient and effective amount of a compoundaccording to claim 1 or
 2. 4. Composition according to claim 3 whereinthe compound of formula (I) is present in proportions of between 0.01and 15 % by weight relative to the total weight of the composition. 5.Composition according to claim 4, wherein the the excipient consists ofan aqueous, aqueous/alcoholic or alcoholic medium.
 6. Process forinducing and stimulating hair growth and for decreasing hair losscomprising applying an effective amount of the composition of claim 3 tothe hair or to the scalp.